Our goals are directed at defining mediators of the adult respiratory distress syndrome. The present focus is the influence of thromboxane (Tx) A2, and to a lesser extent prostacyclin (PG12) and leukotrienes (LT), on inflammatory cell recruitment and pulmonary injury. The primary site of Tx synthesis (extravascular, blood cell or endothelial cell (EC)) in response to common proinflammatory stimuli will be identified. Following lung ischemia induced by microaggregates sized to obstruct or to permit collateral flow and infusion of zymosan activated plasma (ZAP) or infusion of LTC4, TxB2 and 6-keto-PGFlAlpha titers will be quantitated by radioimmunoassay. Identification of the Tx source will be done by using plasma perfused dog lungs, isolated blood cells and EC in culture. Extravascular and EC synthesis in intact lungs will be distinguished by measuring Tx levels in bronchial lavage fluid and vascular perfusates and using ketoconazole, a Tx inhibitor of EC with poor tissue penetrance. The putative role of platelets, WBC and circulating LT in stimulating remote Tx synthesis and lung injury following local injury with HC1 or ZAP will be tested in isolated perfused dog lungs. LTC4 and TxB2 synthesis by injured and noraml lung segments will be measured by radioimmunoassay of lavage fluid, and the effect on cell entrapment and permeability of LT and Tx inhibitors quantitated. The intermediary importance of LT in inducing Tx synthesis will be examined by assay of LT plasma concentration as well as by using three chemically dissimilar LT antagonists. The role of eiconsanoids released from the ischemic lower torso after aortic occlusion, will be related to the formation of microemboli, WBC-LT synthesis, lung Tx synthesis and lung microvascular injury. In ZAP-induced pulmonary TxA2 synthesis and permeability, the intermediary role of WBC-LT will also be tested. The ability of prostenoid agonists and antagonists to moderate cultured EC stress fibers will be quantitated and related to the ability of these same agents to vary albumin flux in the lungs of normal sheep. The role of Tx in remote inflammation after local bronchial instillation of acid or local microvascular injury with ZAP will be examined. Finally, positional changes of the lungs after local acid injury will be used to isolate and test the importance of circulating mediators of Tx synthesis and hydrostatic factors in determining the permeability response of the non-injured lung. Taken together, these studies should define the direct and indirect pulmonary vasotoxic roles of TxA2.